Effect of tocotrienol and tocopherol regulation by the microbiome on colitis-associated cancer.

person Amanda Stafford BioCorteX Inc., New York, NY info_outline Amanda Stafford, Jie (James) Min Lam, Amedra Basgaran, Eva Lymberopoulos, Mohammad Tanweer, Michael Hobbs, James Arney, Dionisios Korovilas, David Delanoue, Stephen Moore, Muhannad Alomari, Nikhil Sharma

Authors person Amanda Stafford BioCorteX Inc., New York, NY info_outline Amanda Stafford, Jie (James) Min Lam, Amedra Basgaran, Eva Lymberopoulos, Mohammad Tanweer, Michael Hobbs, James Arney, Dionisios Korovilas, David Delanoue, Stephen Moore, Muhannad Alomari, Nikhil Sharma Organizations BioCorteX Inc., New York, NY Abstract Disclosures Research Funding BioCorteX Inc. Background: The association between inflammatory bowel disease (IBD) and a higher risk of colorectal cancer (CRC) has been well established, and is commonly attributed to chronic inflammation and a predisposition to genomic instability (Feagins et al., 2009). Independently, an altered gut microbiome has been evidenced in both IBD (Halfvarson et al., 2017) and CRC (Marchesi et al., 2011). It is unknown whether the altered the IBD-associated microbiome is able to directly influence carcinogenesis via an inflammation-independent mechanisms. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. 2,081 stool samples from adults with IBD and 2,000 stool samples from healthy adults were included. Shannon’s Diversity Index was used to consider within-sample diversity, and PERMANOVA and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Differential abundance analysis was used to identify species significantly associated with IBD, and a database built on existing literature was used to consider their metabolic products and interactions with known human oncogenes and tumour suppressor genes. Results: Our results show a clearly separation of the IBD microbiome from the healthy population (PERMANOVA p = 0.01), as well as a collapse in Shannon diversity (p < 2.2e-16). Compared to the healthy microbiome, 79 species were significantly (FDR < 0.01) enriched in the IBD stool microbiome, including: Bacteroides fragilis, Bacteroides vulgatus, Bacteroides uniformis, Escherichia coli, Veillonella parvula, Enterococcus faecalis, Fusobacterium mortiferum, and Fusobacterium ulcerans, all of which have previously been evidenced to be enriched in CRC (Randa et al., 2023, Bi et al., 2022, Du et al., 2022). Conversely, 115 species were enriched in healthy subjects, including several bacteria with probiotic and anti-tumourigeneic potential such as: Segatella copri, Roseburia inulinivorans, Lactobacillus rogosae, and Coprococcus comes (Sarah et al., 2022, Kang et al., 2023, Campisciano et al., 2020, Yang et al., 2019) Two of the bacteria enriched in the healthy group are producers of both delta-tocotrienol and gamma-tocopherol. These vitamin E isoforms have been implicated in suppression of cancer invasion and proliferation (Ya et al., 2008), in part through NFkB signalling (Ling et al., 2012). Conclusions: This work suggests that that IBD-associated microbiome may contribute to colorectal cancer risk via the suppression of vitamin E isoform signalling, a mechanism that is independent from inflammation. This could present a highly targetable way of mediating CRC-risk in the IBD population.